JPS62283967A - Dopamine-beta-hydroxylase inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel compounds that inhibit dopamine-β-hydrakinolase.

Background of the Invention In the catecholamine biosynthetic pathway, thyronone is converted to norepinephrine (NtE) in three steps5. The intermediates are nohytoquinophenylalanino (I) OPA) and dopamine (DA). Dopamine is hydroxylated to norepinephrine by dopamine-β-hydrogynolase (D[31-D) in the presence of oxygen and ascorbic acid.

Suppression of catecholamine activity lowers blood pressure.

reactor. Uniinnorboom, mayo clinical bronze
Dinges (Weinshilbaum, Mayo
Cl1nProc, ), 55.39 (1980) reports compounds that act on atrenalino-like receptors to inhibit catecholamine activity. Also, the catecholamine biosynthetic pathway can be inhibited at any of its three steps, thereby reducing NE concentration. In addition to exerting antihypertensive effects, inhibitors of NE synthesis act as diuretics, natriuretics, cardiotonic agents and vasodilators. Suppression of DBH activity can have the added benefit of avoiding increased DA concentrations, as described by Ehrreich et al., "New Anti-Hypertemporal Drugs," Spectrum Publishing.
at,, ”NewAntihypertensive
Drugs”, Spectum Public-s
hing), 1976, pp. 409-432, it has been found to have selective vasodilatory activity at certain concentrations.

D B I-1 inhibitors also reduce or prevent the formation of gastric ulcers in rats, Hidaka et al., “Catecholamines and Stress,” Usdin et al., eds., Permagon Press, Oxford.
tal, , ”Catecholamine
and Stress”, edit, by Usdin
et al,, PermagonPress,
0x4ord), I 976, pp. 159-I 65 and Osumi et al., Japanese Journal of Pharmacology.
Japan.

J, Pharmacol, ), 23.904 (1
973).

A large number of D I3 H inhibitors are known. these are,
They are usually divided into two types: metal chelators that bind copper in enzymes and phenethylamine analogs. Rosenberg et al., “Essays in Neurochemistry and Neuropharmacology;
-1F4Qj, edited by Yudim et al., John Riley and Sump (Rosenberg et al.
, 'Es5ays in Neurochemistry
ry and Neuropharmacolog
y.

Vol, 4. 'edit by Youdim
et al, , John Wiley &
5ons), 1980, pp. 179-192 and Goldstein, Pharmacological Reviews (Go
ldstein, Pharmacol, Rev.
).

+ 8(1), 77(196G) reported a DBF-1 inhibitor. The former is because many powerful BH inhibitors have hydrophobic side chains comparable in size to the aromatic ring of DA, and the introduction of terminal hydroxyl groups in the 4- to 6-carbon side chains of phenethylamine analogues is highly effective. It has been reported that the scales produced a strong inhibitory agent.

Known D B I-r inhibitors include (a) 5-alkylpicolinic acids [Suda et al.
l, , Chem, Pharm, Bull, ), I
7゜2377 (+969); Umezawa et al., Biochemical Pharmacology
al.

Biochem, Pharmacol, ), supra 9.
35 (1969); Hida Chikara et al., Molecular Pharmacology (1) (Idaka et al., M.
o1. Pharmacol, ), 9°172 (19
73); Miyan et al., Chemical and Pharmaceutical Sciences.

et al, , Chem, Pharm, Bull
), 26.2328 (+978); Miyan et al., Heterocycles (Miyan.

eLal, , Heterocycles), 14.
755 (1980): Claxton et al., European Journal of Pharmacology (C1axto
n et al.

Eur, J. Pharmacol, ), 37.
l 79 (1976) Reference I, Regulation f: b) I3RL 8212
1axton et al., Eur, J.
Pharmacol, ).

37.179 (1976)] (c) l-Alkylimidazole-2-thiols [
Hanlon et al., Life Sciences
et al, , Life Sci, ), 1
2, 417 (1973); Fuller et al.
etal, , Adv, Enzyme Reg
ul, ), 15.267 (1976)] (d) Substituted thioureas [Johnson et al., Journal
Talented Pharmacology and Suberimental Therapeutics (Johnson etall)
, J., Pharmacol, Exp., Ther.
), l68.

229 (1969)] and (e) benoloxyamine and hensylhydranone [Creveling et al.
.

13iochim, Lliophs, Ac
ta), 6 4, l 2 5 (1962),
Frehering et al., Biohimica Engineering, Biophysica Engineering,
Acta (Creveling et at,,Bio
chim.

Biophs, Acta), 8,215 (+962
): Van Der 5choot et al., Journal of Pharmacology and Experimental Therapeutics (Van Der 5choot
et al.

J, Pharmacol, Exp, Ther.
), l 41, 74 (1963); Bloom, Ann's of the New York Academy of Sciences.

Ann, N., Y., Acad, Sci.),
IO 7, 878 (1963)].

As can be seen, all of the above compounds except benoloxyamine and penzylhydranone are based on their inhibitory effect on metal chelating properties. Imidazole-2
-Alkyl derivatives of thiols are more potent, probably due to non-specific interactions of the alkyl substituents of the enzyme.

Benzyloxyamine and benzylhydranone are phenethylamine analogs and apparently act as competitive inhibitors.

In addition to the compounds mentioned above, Runti et al.
et al, ,+1 Parmaco Ed,
Sci, ).

16.260 (1980) reported that other fusaric acid derivatives and congeners inhibit D B tl. These include phenylpicolinic acid, which has twice the inhibitory activity of fusaric acid, and 5-(4-chlorobudel)picric acid, and substituted amides of fusaric acid and fusaric acid derivatives and 5-butyloylbicolinate,
Other compounds such as amides of 5-aminopicolinic acid and 5-hydrazinopicolinic acid and their derivatives are mentioned.

Hida Chikara et al., Molecular Pharmacolon () [1d
aka et al., Mo1ecu
lar Pharmacology).

See, 172-+77 (1972), 5-(3,lI-
reported that nobromobutyl)picric acid and 5-(dimethyldithiorubamoylmedyl)picric acid are Dr3[+ inhibitors.

Bupicomide, 5-(n-butyl)picolinamine, has been described by Erreich et al., “Two Anti-Hypertensive Drugs,” Spectrum Publications (Eh
rreich et al., “New Anti
“hypertensive Drugs”, Spe.
ctrum Publications), 1976.
D with antihypertensive activity according to pages 409-432
It has been reported that it is a BH inhibitor.

European Patent Application No. 125033 describes a series of 1-phenyl and! with a mercapto or alkylthio group in the 2-position. -phenylalkyl imidazole compounds are disclosed. These compounds are described as having DBH inhibitory activity.

U.S. Pat.
discloses several medylviridine derivatives isolated from the fermentation broth of a strain of. These compounds are D +3
Inhibits II activity.

U.S. Pat. No. 4,532,331 discloses various 1-benzyl-2-aminomethylimidazole derivatives that inhibit D +3 H activity, and pharmaceutical compositions containing these derivatives and inhibits D B I-1 activity. It includes methods of using these derivatives to.

The non-specific and often toxic nature of known DBH inhibitors has precluded clinical use of these compounds. For example, fusaric acid is known to be hepatotoxic. For example, Terasawa et al., Noyapanese Circulation Journal
tal, Japan, Cir, J.).

35.339 (+971) and its cited references.

It is likely that the picric acid structure interacts nonspecifically with many metalloproteins and enzymes, resulting in the various side effects observed.

Formula: [where n is 0 and X is hydrogen, CH3, OCH3, o
CH, Cr-t,,OC[42CH2CI-1(C
H3) 2, Br.

4-aralkyl-substituted-1,2,44-lyazole-3-thiols shown as CQ, ■, CP 3, No2 are CO011 or combinations thereof, n is 1 and X is hydrogen] is synthesized into. for example,
Chemical Abstracts 76.105 Reference 1 q0 Certain 1-aralkyl-substituted-1,2,4-1 lyazole-5-thiols have been previously produced. These known compounds have the formula:

1, where n is 0 or 1 means 1]. For example, Chemical 11161, Chemical 75,
1.162+4, see 70,330.

However, 4-aralkyl-substituted-1,2,4-triazole-3-thiol and 1-aralkyl-substituted-1
, 2,4-triazole-5-thiol compounds, the above documents disclose that these compounds are dopamine-β-
Does it have activity as a hydroxylase inhibitor?
There is no suggestion that the reduction of dopamine-β-hydrokinelase activity would be of any therapeutic utility in treating diseases such as hypertension. These compounds are used as reagents in photographic and electrographic processes and analytical methods. Some of these compounds are also used as fungicides, herbicides and insecticides. Additionally, certain of these compounds have been shown to suppress tumors in mice caused by the bacteria that causes Hansen's disease.

SUMMARY OF THE INVENTION The present invention provides that D B I-I is substituted l-aralkyl-1°2.1-triazole-5-thiol and substituted! -Aralkyl-1.2.4-triazole-5-alkylthiol compounds belong to the discovery that this is inhibited by compounds. These compounds are potent and produce long-lasting Dr311 inhibition.

Preferred compounds of the invention and compounds included in the pharmaceutical compositions and methods of the invention include 1-7\nnor to 1. ．． 2.4-triazole-5-thiol, 1
-(3'-fluorobenzyl-1°2,,1-triazole-5-thiol and !=(3,5'-nofluorobenzyl)-1,2,,4-triazole-5-thiol.

In one embodiment of the invention, substitution! -Aralkyl-1,2,4-triazole-5-thiol and substituted 1-aralkyl-152,.1-triazole-5-alkylthiol compounds are provided.

The present invention provides substituted l-aralkyl-1,2,4-triazole-5-thiols and substituted l-aralkyl-1,2
, 4-1 = a novel method for producing intermediates useful in the production of lyazole-5-alkylthiol compounds.

The present invention is also useful for the treatment of D[
The present invention relates to compounds for use in inhibiting 3If activity.

Also encompassed by the invention are pharmaceutical compositions characterized by comprising a compound useful in the methods of the invention and a pharmaceutical carrier.

DETAILED DESCRIPTION OF THE INVENTION The compound of the present invention that suppresses D B r-I has the formula (1):
[Wherein, n is O-5, R is hydrogen or alkyl having 1 to 4 carbon atoms, and X is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, CN, NO2, S 02 N H2, COO14
, Cl-1o, O[-1, CH201-(, carbon number 1
~4 Alcogine, CF3.5o2CI-13, S 0
2 CF *f, 1.1 inch r I"l-r 'LT-,
(*EF I ~"; )e +-H/' tint any combination of up to 5 substituents available for the conclusion] (provided that n is 0 or 1 and is hydrogen) or any pharmaceutically acceptable salt thereof is a hydrate.

As used herein, halogen means bromo, fluoro, chloro or iodo.

Suitably R is alkyl having 1 to 4 carbon atoms, preferably R is hydrogen. Suitably n is 0.2.3 or 4, preferably n is 1. Preferably, X
is a synthetically accessible combination of substituents on two sides, and preferably X is one substituent.

Formula (■): [where n is 0 to 5, R is hydrogen or alkyl having 1 to 4 carbon atoms, and X is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, (, N, NO2, So, N+ -[2, C0OH,
C1[0,ON, Ct120H1 Alcoquino with 1 to 4 carbon atoms, CF3, So2C11,, SO20[;"3 seems to be COx CatI 2 a+ 1 (a is 1 to 5)
or any combination of up to five substituents thereof which can be obtained synthetically]
The acceptable salts may be hydrated or included in the pharmaceutical compositions of the present invention or the pharmaceutical compositions used in the methods of the present invention.

Formulas ([) and (II) include tautomers of compounds in which R is hydrogen, ie, compounds in which the triazole moiety has any of the formulas.

Compounds of [2ε]] and [■L' in which n is 1 are produced from the corresponding benzaldehydes by the method shown in Reaction Formula I below. starting material f
The benzaldehydes are known and are described in the above-mentioned literature or are readily available.

Reaction formula (2) is an X-substituted JJ (X is the above formula (
benzaldehydes (A) having the same meaning as I) and t
- shows the reaction of butyl carbazate in a 41 solvent such as hexadiene.

Then, substituted monobutoquinocarbonylhydranones (C
) in an inert organic solvent such as ethanol, methylene chloride, chloroform, tetrahydrofuran, ethyl acetate or ethyl ether, preferably methanol, using a hydrogenating agent such as palladium (preferably 10%) on carbon. Butoquinocarbonyl hydrazones (B)
Produced by hydrogenation of

Then, the L-butquin carbonylhydranone Pl'1
2-substituted-
1-t-Butquinecarbonyl-1-t-butyldiocemicrubazide compound (D) i=Zero.

Compounds of formula (+) and (II) in which R is hydrogen are then treated with the 2- Substituted-1-L-butoquinocarbonyl-・1-
Produced by cyclization of t-butylthiosemicarpats.

Reaction formula I (E) Using boron tribromide or hydrobromic acid, the corresponding formula (E
) of the 1-alkoxyaralkyl-substituted-1゜2.4-triazole-5-thioyl compound of the present invention! -Hydroxyaralkyl-substituted-1,2,4-triazole-5-thiols are obtained.

Compounds in which R is a medyl group can be substituted with the corresponding l-aralkyl substituents included in compounds of formula (E) using methyl iodide in methanol by known methods.

2.4-) Produced by alkylation of lyazole-5-thiols. Other alkyl halides such as methyl bromide or methyl chloride can be substituted for methyl iodide in a suitable solvent. Furthermore, a compound in which R is an alkyl group other than methyl can be prepared by combining the corresponding 1-aralkyl-substituted-1°2,4-triazole-5-thiol compound of formula (E) with an alkyl group such as butyl iodide in a suitable solvent. It is prepared by reaction of a halide to obtain the desired 1-aralkyl-substituted-1,2,4-triazole-5-alkylthiol compounds of the present invention.

In reaction formula (2), n is summer, but n can be O-5. Preferably, the compound in which n is 0 is prepared from substituted phenylhydranones in place of t-butoxycarbonylhydrazines (C) in the method of Reaction Formula (1). The starting substituted phenylhydrazines are known and can be produced by known methods. Compounds in which n is 2, 3, 4 or 5, benzaldehydes (A) are converted into phenethylaldehyde, 3-phenyl-1-propionaldehyde or 4-phenyl-! - Produced by the method of reaction formula r, except that phenylalkyl (alkyl having 1 to 4 carbon atoms) aldehydes such as butyraldehyde are used instead.

Substituted 1-aralkyl-1,2,4-)riazole-5-thiols and substituted l-aralkyl-1,2,
When producing a 4-triazole-5-alkylthiol compound, the formula: [where n is θ~4, X is hydrogen, halogen, carbon number 1~
Alkyl of 4, CI'JSNo,, S Ot N H2
,COOHlCI(OlOr(,CH,OH,1 carbon number
~4 alkoxy, CF3, S Ot CHz, So,
CF3 or C0tC, H2, +1 (a is 1 to 5)
or any combination of up to five substituents thereof synthetically available and Z is C=NNHCO,C(CF
13) 3, CI-[*NHNHCO2C (CI-13)
3 or I (provided that n is 0 and Z
is C= N N I-I COt C(C[(3) z
or Cl-12NHNHCOtC(CH3)3).

Formula: [wherein, X is halogen, alkyl having 1 to 4 carbon atoms, CN
S No,, SO, NH,, co o
t, CI-10.

OH, CH20H, carbon number 1 to 4 (7) 7/l/niaxy, CF3, S Ot CH3, S Ot CP 3 or C0tC,1 (2a+t (a is 1 to 5) or its 5 that can be synthesized by hand) Novel intermediates are synthesized in the preparation of the D B H inhibitors of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of this invention are formed with strong or moderately strong organic or inorganic acids by known methods. For example, combining the base with an inorganic or organic acid,
Either react in a water-miscible solvent such as ethanol and allow the salt to be isolated by removing the solvent, or react directly or in a water-immiscible solvent in which the nucleic acid can be dissolved, such as ethyl ether or chloroform. The desired salt is separated by removal of the solvent. Examples of such salts encompassed by the present invention include:
Maleate, fumarate, lactate, sulfate, methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate, phosphorus Includes acid salts and nitrates.

Compounds of formula (1) and (II) inhibit D Bt activity, making the compounds therapeutically useful as diuretics, natriuretics, cardiotonic agents, antihypertensive agents and vasodilators, and antiulcerogenic agents. have sex. In vitro by standard methods for analyzing the conversion of tyramine to octopamine in the presence of DB I-1.

Compounds of the invention that have been tested for D B H inhibition in , compounds included in the pharmaceutical compositions of the invention and compounds useful in the methods of the invention are shown in Table 1.

Noei, J., Bisano, et al.
tal, , Biochim Biophys, A
cLa), ±3,566 to 682 (+960). Octobamine was oxidized to p-hydroxybenzaldehyde with sodium periodate and then analyzed by spectrophotometric absorbance measurements at 330 nm. In Table 1, inhibition is expressed as the molar concentration of compound at which the D B H activity is halved (ICso). This test revealed that the fusaric acid had a TO of 8XIO-'M.

Table 1 In addition, 100ff9/to9 in spontaneously hypertensive rats
1-benzyl-1,2,4-triazole-
5-of thiols! The suspension or solution was administered orally, and the mean arterial blood pressure was measured for 260 minutes using an indwelling cannula inserted into the caudal artery. When compared to vehicle-treated controls, blood pressure in animals treated with the compound increased after treatment 20.
After minutes it was about 5% lower than that of the control. Blood pressure in animals treated with the compound continued to decrease until it reached its nadir, approximately 20% lower than controls, 240 minutes after compound treatment.

Similarly, 1-(3'-fluorobenzyl-)-1,2°4-triazole-5-thiol showed an approximately 20% reduction in blood pressure 1 hour after intraperitoneal administration of 9 at 507 g/g. At the end of blood pressure monitoring, blood pressure in treated animals was still approximately 20% lower than controls.

The compounds of formula (II) are formulated into convenient dosage forms such as capsules, tablets or injections.

Solid or liquid pharmaceutical carriers can be used.

Solid carriers include starch, lactose, carnoum sulfate,
White china clay, sugar, talc, gelatin, agar, pectin,
Includes acacia, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut butter, olive oil, saline and water. Similarly, carriers or diluents include any delay materials such as glyceryl monostearate or glyceryl distearate alone or in combination with waxes. Although the m of the solid support can vary widely,
Preferably from about 25 to about 17 doses per dosage unit. If a liquid carrier is used, the J,! The I product may be a sterile injectable solution such as a noronob, elixir, emulsion, soft geladine capsule, ampoule, or an aqueous or non-aqueous j13iQ solution.

The pharmaceutical preparations are manufactured according to conventional formulation techniques, including mixing, granulating and, optionally, compressing or mixing, filling and dissolving the ingredients for tablets to obtain the desired oral or parenteral product. Ru.

In said pharmaceutical dosage unit, the dosage of the compound of formula (II) according to the invention may be between 0.1 and 100 vy/ml of the active compound!
? , preferably at an effective and non-toxic amount selected from the range of 1 to 50 mg/kg.

Administer the selected dose orally, rectally, or by injection or continuous infusion, 1 to 6 times, in human patients in need of DI3)1 suppression.

Oral dosage units for humans preferably contain 1 to 500
mg of active compound. Parenteral administration is preferred using lower doses. However, oral administration may be used at higher dosages if safe for the patient and convenient.

The method of the present invention for inhibiting D[31-1 activity in mammals, including humans, comprises internal administration of an effective amount of a compound of formula (II) for inhibiting D[3t] to a patient in need of such inhibition. consists of doing.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 l-(3'-Fluorohenonor)-1,2,4-triazole-5-thiol 3-fluorobenzaldehyde 6.219 (0.05 mol) and t-butylcarbamate 6619 (0.05 mol) in hexane Heat the solution under reflux for 30 minutes in 50 mQ. The mixture was cooled in water and the product was filtered and recrystallized from ethanol to yield I-(3'-fluorobenzaldehyde)-17butoquinocarponylhydrazone8.
799 (74%).

Melting point 165-168 ° C0 Mixture of 1.029 (4.28 mmol) of 1-(3'-fluorobenzaldehyde)-1-butoquinocarbonylhydrazone and 220 m9 of lO% paranoum carbon in methanol 40 TIQ under hydrogen atmosphere (401 bs) Shake for 1 hour. The reaction mixture was filtered and the solvent was removed under reduced pressure to give +-(a'-fluorohenonor)-
2-l-butoquinocarbonylhydranone 1.00g (9
7%).

2.29 g (9,53 mmol) of 1-(3'-fluorobenzyl-2-butoquinocarbonylhydrazone) and t-butylisothionoane-1-2,=11zQ(
A solution of 19.1 mmol) in ethyl acetate 151Q is refluxed for 7 hours. The solvent was removed under reduced pressure, the residue was triazolized with hexane, the product was filtered, dried and 1-L-
Butoquinocarbonyl-2-(3'-fluorobenzyl-4-t-butyldiocemic rubazite, 28 g (3
8%).

1-t-Butoquinocarbonyl-2-(3'-fluorobenzyl-.I-t-butyldiosemicarbanide 1.
A solution of 289 (3.60 mmol) in 98% formic acid 1stQ is refluxed for 4 hours and the solvent is removed under reduced pressure. The residue was dissolved in methylene chloride-ethyl acetate (80:20) and purified by gel chromatography to give +-(3'-fluorobenzyl-1,2,11').
-triazole-5-thiol 16;) 1g (22%
). Melting point 155-156°C3 Example 2 1-(3',5'-difluorobenzyl)-1,2
゜4-triazole-5-thiol 90% formic acid 50. A mixture of 50 g (0,0359 mol) of 3,5-nofluorohenzonitrile and Ufuichi catalyst powder in yL2 was stirred under reflux for 2 hours, the catalyst was filtered,
Wash with hot water and hexane. Separate the hexane layer;
The aqueous solution is extracted four more times with hexane. The combined hexane extracts were washed with water and brine, dried, and the solvent removed to give 3.5-7 fluorobenzaldehyde.
71': 66%).

3.5-Difluenzaldehyde 3.379 (0,
0237 mol) and L-butylcarbazate 3.13
A solution of g (0.0237 mol) in 6OmQ hexane is heated under reflux for 30 minutes. The mixture was cooled in water, the product was filtered and recrystallized from ethanol to yield I-(3'
, 5'-nofluorohenzaldehyde)-2-t-butoxycarbonylhydrazone 3.52 g (58%) are obtained. Melting point: 190-191°C.

Under hydrogen atmosphere (421bs,) methanol 1 out of 50
-(3',5'-difluorobenzaldehyde)
-1-butoxycarbonylhydrazone 3.49g (13
6 mmol) and 10% palladium-carbon 300 m9
The mixture is shaken for 45 hours and the catalyst is filtered off. The solution was added again to 1 il of 10% Paranoum Carbon 400M.
and shaken under hydrogen atmosphere for 15 hours. The reaction mixture was filtered and the solvent was removed under reduced pressure to give 1-(3',
3.34!1 l (95%) of F1'-difluorohenol-2-tert-butquinecarbonylhydranone is obtained.

1-(3',5'-lefluorobenzyl)-2-
-butoquinocarbonylhydranone 3.229 (125
mmol) and butylisothionoanate 1.6
A solution of z&(12.6 mmol) in 30 ur2 of ethyl acetate is refluxed for 17 hours. A further 2.7a of di-butyl isothionoanate is added and the mixture is refluxed for 5 hours. The solvent was removed under reduced pressure, the residue was triazolized with hexane, the product was filtered and dried to give 1-t-butoquinocarbonyl-2-(3',5'-difluorohennor)-4.
-t-butylthiosemicarpant 3.03g (65%)
get.

2.98 g (7.98 mmol) of 1-1-butquinolsulfonyl-2-(3',5'-difluorohennor)-4-1-butylthiosemicarpant in 40 ml of 98% formic acid (
The solution is refluxed for 4 hours and the solvent is removed under reduced pressure. The residue was triazolized with ether and the resulting solid was filtered once. The solid was dissolved in dichloromethane-edyl acetate (80:20) and purified by chromatography to give 1-(3',5'-difluorohennor) to 1,2,. 1-triazole-5-thiol 4
Obtain 07*9 (22%). Melting point 188-189°C0 Example 3 ■-Benzyru 1.2. =1-Triazole-5-thiol The title compound is obtained using the method of Example 1 but using henzaldehyde instead of 3-fluorobenzaldehyde.

Example 4 1-(3',5'-difluorohennor)-5-methylthio-1,2,41 riazole 1-(3',5'-difluorohennor)-1,2
The title compound is obtained by reacting 4-triazole-5-thiol (prepared similarly to Example 2) with methyl iodide and sodium methoxyd in methanol by known methods.

Example 5 1-(3'-Fluorophenyl)-1,2,4-triazole-5-thiol In the method of Example 1, 1-(3'-fluorobennor')-2-t-butoxycarbonylhydrazone 3
- instead of fluorophenylhydranone, the title compound is obtained.

Example 6 l-(3'-phenyldobropyl)-1°2.4
-Triazole-5-thiol In the method of Example 1, 3-phenyl-! -Preparation of the title compound using propionaldehyde.

Example 7 1-(3'-Noanohennor)-1,2,1-triazole-5-thiol The method of Example 1, but using 3-noanol\zaldehyde instead of 3-fluorobenzaldehyde. The title compound is obtained.

Example 8 l-(3′-nitrophenyl)-1,2,1-triazole-5-thousandol In the method of Example I, l-(3′-fluorobenzyl-2-j-butoquinocarbonylhydranone) Substituting 3-nitrophenylhydral instead gives the title compound.

Example 9 l-(4'-methylsulfonylbenzyl)-1°2.
4-Triazole-5-thiol The title compound is obtained in the manner of Example 1, using 4-methylsulfonylbenzaldehyde instead of 3-fluorobenzaldehyde.

Example 10! -(4'-carboethoxybenzyl)-1,2゜4
-Triazole-5-thiol Using the method of Example 1 but using 4-carboethoxybenzaldehyde instead of 3-fluorobenzaldehyde, the title compound is obtained.

Example 11 An oral dosage form of a compound of the invention is prepared by sieving, mixing and filling into hard gelatin capsules the following ingredients.

Ingredient Weight (g) 1-(3'-fluorobenzyl)-1,2,4-triazole-5-thiol 50 Magnenium stearate 5 Lactose
75 Example 12 Sucrose, calcium sulfate dihydrate, and the following I-aralkyl substituted 1.2° 4-triazole-5-thiol are mixed with a 10% gelatin solution in the indicated proportions and granulated. . The wet granules are sieved, dried, mixed with starch, talc and stearic acid, sieved and compressed into tablets.

Ingredients: 1-(3',5'-difluorobenzyl)-1
,2,4-triazole-5-thiol
100 butts? Calcium sulfate dihydrate
+50ay sea*
2 (Lv9 starch 10
11g Talc 5m9 Stearic acid 3H Example l
1 l-(3',5'-difluoro-4'-hydroquinbenzyl)-1,2,4-triazole-5-thiol hydrochloride 75 shoulder 9 was dispersed in 25 standard saline and prepared for injection. SmithKline Beckman Corporation Patent Applicant Characterizing Things

Claims (15)

[Claims] (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n is 0 to 5, R is hydrogen or alkyl having 1 to 4 carbon atoms, and X is hydrogen, halogen, or alkyl having 1 to 4 carbon atoms. ,CN,NO_2,SO_2NH_2,COOH,
CHO, CH_2H, OH, alkoxy having 1 to 4 carbon atoms, CF_3, SO_2CH_3, SO_2CF_3 or CO_2C_aH_2_a_+_1 (a is 1 to 5)
or any combination of up to five synthetically available substituents thereof] (excluding compounds where n is 0 or 1 and X is hydrogen) or any of them. Pharmaceutically acceptable salts or hydrates. (2) The compound of item (1) above, wherein R is hydrogen. (3) The compound according to item (2) above, wherein n is 1. (4) 1-(3'-fluorobenzyl)-1,2,4-
triazole-5-thiol or 1-(3',5'-
difluorobenzyl)-1,2,4-triazole-5
- The compound of item (3) above which is a thiol. Formula (5); ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n is 0 to 5, R is hydrogen or alkyl having 1 to 4 carbon atoms, and X is hydrogen, halogen, or alkyl having 1 to 4 carbon atoms. ,CN,NO_2,SO_2NH_2,COOH,
CHO, CH_2OH, OH, alkoxy having 1 to 4 carbon atoms, CF_3, SO_2CH_3, SO_2CF_3 or CO_2C_aH_2_a_+_1 (a is 1 to 5
) or any combination of up to five synthetically available substituents thereof] or a pharmaceutically acceptable salt, preferably a hydrate thereof, and a suitable pharmaceutical carrier. A pharmaceutical composition characterized by: (6) The compound is 1-benzyl-1,2,4-triazole-5-thiol, 1-(3'-fluorobenzyl-
1,2,4-triazole-5-thiol or 1-(
The pharmaceutical composition according to item (5) above, which is 3',5'-difluorobenzyl)-1,2,4-triazole-5-thiol. (7) Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n is 0 to 4, X is hydrogen, halogen, carbon number 1 to
4 alkyl, CN, NO_2, SO_2NH_2, C
OOH, CHO, OH, CH_2OH, alkoxy with prime numbers 1 to 4, CF_3, SO_2CH_3, SO_2CF
_3 or CO_2C_aH_2_a_+_1 (a is 1-5) or any combination of up to 5 synthetically available substituents thereof and Z is
2C(CH_3)_3, CH_2NNHCO_2C(C
H_3)_3 or ▲There are mathematical formulas, chemical formulas, tables, etc.▼
] A compound represented by (where n is 0, X is H and Z is C
=NNHCO_2C(CH_3)_3 or CH_2N
except for compounds that are HNHCO_2C(CH_3)_3). (8) 1-(3'-fluorobenzaldehyde)-t-
butoxycarbonylhydrazone, 1-(3'-fluorobenzyl)-2-t-butoxycarbonylhydrazine,
1-t-Butoxycarbonyl-2-(3'-fluorobenzyl)-4-t-butylthiosemicarbazide, 1-(
3',5'-difluorobenzaldehyde)-t-butoxycarbonylhydrazone, 1-(3',5'-difluorobenzyl)-2-t-butoxycarbonylhydrazine, 1-t-butoxycarbonyl-2-(3', 5'-
(fluorobenzyl)-4-t-butylthiosemicarbazide or 1-t-butoxycarbonyl-2-benzyl-
Said No. (7) which is 4-t-butylthiosemicarbazide
compound of term. Formula (9): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is halogen, alkyl having 1 to 4 carbon atoms, CN
, NO_2, SO_2NH_2, COOH, CHO, O
H, CH_2OH, alkoxy having 1 to 4 carbon atoms, CF_
3, SO_2CH_3, SO_2CF_3 or CO
_2C_aH_2_a_+_1 (a is 1 to 5) or any combination of up to 5 synthetically available substituents thereof]. Formula (10): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Formula (X) characterized by consisting of hydrogenation of a compound represented by [In the formula, X and n have the same meanings as below]: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X) [In the formula, X is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, CN, NO_2, SO_2NH_2, COOH, CH
O, CH_2OH, OH, alkoxy having 1 to 4 carbon atoms,
CF_3, SO_2CH_3, SO_2CF_3 or CO_2C_aH_2_a_+_1 (a is 1 to 5) or any combination of up to 5 synthetically available substituents thereof and n means 1 to 5] or any of them A method for producing a pharmaceutically acceptable salt or hydrate of (11) The compound to be produced is 1-benzyl-2-t-butoxycarbonylhydrazine, 1-(3'-fluorobenzyl)-2-t-butoxycarbonylhydrazine or 1-(3',5'-difluorobenzyl) -2-t-
The method for producing item (10) above, which is butoxycarbonylhydrazine. (12) In an inert organic solvent, react t-butyl isothiorianate with a compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n and X have the same meanings as below] Formula (XX) characterized by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XX) [In the formula, n is 1 to 5, X is hydrogen, halogen, carbon number 1 to
4 alkyl, CN, NO_2, SO_2NH_2, C
OOH, CHO, CH_2OH, OH, alkoxy having 1 to 4 carbon atoms, CF_3, SO_2CH_3, SO_2C
F_3 or CO_2C_aH_2_a_+_1(a
means any combination of 1 to 5) or up to 5 synthetically available substituents thereof] or a method for producing a pharmaceutically acceptable salt or hydrate thereof. . (13) The compound produced is 1-t-butoxycarbonyl-2-benzyl-4-t-butylthiosemicarbazide, 1-t-butoxycarbonyl-2-(3'-fluorobenzyl)-4-t-butylthio The method for producing the above item (12), which is semicarbazide or 1-t-butoxycarbonyl-2-(3',5'-difluorobenzyl)-4-t-butylthiosemicarbazide. (14) In the presence of a strong acid, a compound represented by the formula (XXX I): ▲Mathematical formula, chemical formula, table, etc.▼(XXX I) [wherein X and n have the same meanings as below] is cyclized. , when R is alkyl having 1 to 4 carbon atoms, the formula (XXX) is characterized by alkylating the compound of formula (XXX) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XXX) [In the formula, n is 0 to 5, X is hydrogen, halogen, carbon number 1 to
4 alkyl, CN, NO_2, SO_2NH_2, C
OOH, CHO, CH_2OH, OH alkoxy having 1 to 4 carbon atoms, CF_3, SO_2CH_3, SO_2CF
_3 or CO_2C_aH_2_a_+_1 (a is 1 to 5) or any combination of up to 5 synthetically available substituents thereof and R means hydrogen or alkyl having 1 to 4 carbon atoms] or A method for producing a pharmaceutically acceptable salt or hydrate thereof. (15) The compound produced is 1-benzyl-1,2,4
-triazole-5-thiol, 1-(3'-fluorobenzyl)-1,2,4-triazole-5-thiol or 1-(3',5'-difluorobenzyl)-1,
Said (1) which is 2,4-triazole-5-thiol
4) Manufacturing method.